1. Field of the Invention
The present invention relates to the modulation of aqueous humor outflow by targeting cadherins between Schlemm's canal cells and methods of treating glaucoma by employing cadherin inhibitors.
2. Description of the Background
Glaucoma is the second leading cause of blindness in the United States. (Quigley H. Br J. Opthalmol. 1996; 80:389-393.) The most common form, open-angle glaucoma, is characterized by elevated intraocular pressure (IOP) that compresses nerve axons resulting in loss of ganglion cells and subsequent loss of vision. (Quigley H et al. Am J. Opthalmol. 1983; 95:673-691) IOP is maintained by a balance between production and removal of aqueous humor from the eye. A reduction in removal aqueous humor elevates IOP and often leads to glaucoma. (Rohen J. Opthalmol. 1983; 95:673-691) The primary pathway in humans for removal of aqueous humor consists of the trabecular meshwork (TM) and the canal of Schlemm (SC). The majority of resistance to outflow of aqueous humor is generated deep in the TM (juxtacanalicular region) near or at the inner wall of SC. (Grant WM. Arch Opthalmol. 1963; 69:783; Bill A, Maepea O. Mechanisms and routes of aqueous humor drainage. Philadelphia: WB Saunders, 1975:206-226).
Intercellular adhesion is mediated by specific cell surface adhesion molecules. Two classes of transmembrane cell-cell adhesion molecules are present in adherens junctions of endothelium. Associated with VE-cadherin in discrete but separate domains in the adherens junction is PECAM-1 (CD31), which is a member of the immunoglobulin superfamily of adhesion molecules. (Ferrero E, et al FEBS Letters. 1995; 374:323-326). While calcium-independent intercellular adhesion has been shown to be through PECAM-1, VE-cadherin interactions are calcium-dependent. Cadherins mediate cell-cell adhesion through specific protein-protein interactions of cytoplasmic domains (Nose A, et al Cell. 1990; 61:147-155). The conserved cytoplasmic domain of cadherins is required for function and deletion of the cytoplasmic domain has been shown to inhibit cell-cell adhesion. (Kintner C Cell. 1992; 69:225-236). A family of intracellular proteins termed the catenins (α-catenin, β-catenin, γ-catenin, p120ctn) is associated with the cytoplasmic domain of cadherins and links the complex to cortical actin filaments (Adams C Curr Opinion Cell Biol. 1998; 10: 572-577). While αcatenin is the direct linkage with actin filaments, β-catenin regulates the association of the cadherin complex with the cytoskeleton and p120ctn regulates high affinity binding of the complex between adjacent cells (Roura S et al J. Cell Biol. 1999; 274:36734-36740; Thoreson M et al Cell Biol. 2000; 148:189-202). The catenins function in the dynamic regulation of cadherin adhesive function. Tyrosine and serine/threonine phosphorylation of the cadherin/catenin complex modulate the adhesive function of the adherens junction complex by decreasing the affinity of cadherin for an adjacent cadherin or the affinity of the cadherin/catenin complex with the F-actin cytoskeleton (Roura S et al J. Cell Biol. 1999; 274:36734-36740; Rajasekaran A, et al J. Cell Biol. 1996; 132:451-463). Studies suggest that the catenins also function in the assembly of ZO-1 into tight junctions by mobilization of the ZO-1 from the cytosol to the cell surface (Rajasekaran A, et al J Cell Biol. 1996; 132:451-463). Therefore, regulation of the balance of multiple cell-cell adhesion molecules in response to soluble and mechanical factors is likely to play a role in control of complexity and interdependence of cell junctions between SC cells (Noria S et al Circ Res. 1999; 85:504-514).
In general, monoclonal antibodies against the first amino terminal repeat of VE-cadherin (that include EC 1) increase permeability of endothelial monolayers in vitro and in vivo (Corada M, et al Blood 2001; 97:1679-1684). Upon treatment with anti-VE-cadherin antibodies, VE-cadherin redistributes on cell surface away from intercellular junctions but does not change the localization of CD31 or tight junction proteins. Thus, VE-cadherin is a key protein involved in regulating permeability of vascular endothelial (Haselton F, Heimark R. L. J Cell Physiol. 1997; 171:243-251; Wong R, et al Am. J. Physiol. 1999; 276:H736-H748).
Currently, the primary goal in the treatment of people with glaucoma is to reduce intraocular pressure either by decreasing inflow or increasing outflow of aqueous humor. There are several currently used approaches to treat glaucoma. Current pharmacological treatments in most cases insufficiently reduce pressure in those with glaucoma. Second, no commonly used method targets the primary outflow structures of the eye; a location of pathology in most glaucomas. Third, laser trabeculoplasty, the most common surgical intervention, involves damaging trabecular meshwork tissue that results in increased remodeling and increased outflow that only lasts for a short time (usually months). Fourth, if all the above do not lower intraocular pressure, a major surgical procedure, trabeculectomy, is performed. This surgical procedure has many complications associated and is only marginally successful in most cases, lasting 1-5 years.
There remains an urgent need for new and effective therapies to treat glaucoma.